tbuckley/cabot-search huggingface dataset:
ATRT-06. Atypical Teratoid Rhabdoid Tumors (ATRT): results from a Single Institution in Brazil - São Paulo University
Authors: Juliana Silveira Barreto, Karen Nirit Melo Gomez, Alvaro Pimenta Dutra, Alessandra Milani Prandini De Azambuja, Lilian Maria Cristofani, Felipe Hada Sanders, Carlo Petito, Helena Espindola Baraldi, Eduardo Weltman, Suely Fazio Ferraciolli, Fernando Pereira Frassetto, Leandro Tavares Lucato, Sérgio Rosemberg, Vicente Odone Filho
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVES: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly malignant tumor of the central nervous system with poor prognosis. Nowadays, multimodal management, including surgery, chemotherapy (CMT), radiation therapy (RT) and Bone Marrow Transplantation (BMT). The aim of this study was to assess the experience and survival in a center of reference of treatment in childhood cancer in Brazil. PATIENTS AND METHODS: Medical records of AT/RT patients who underwent surgery from 2008 to 2020 at a center of childhood cancer treatment (ITACI) in São Paulo University were retrospectively reviewed and statistically analyzed. RESULTS: Eight patients (2 males and 6 females) were presented with AT/RTs. Median age during presentation was 22 months (range, 0 - 6 years). Seven patients (88%) were &amp;lt; 18 months and one patient were &amp;gt;18 months. Tumor location was supratentorial in four patients, infratentorial in 2 patients. Kidney disease as the primary diagnosis in 2 patients (25%). Surgical treatment was performed in 4 patients. Seven children underwent total CMT and 3 children were treated with RT. Only 3 patients underwent Autologous Bone Marrow Transplantation (ABMT). The chemotherapy management protocol of the patients was variable: 2 patients received the EU-RHAB protocol, 2 patients received the HEAD START III protocol, 3 patients received chemotherapy in the ICE regimen (Ifosfamide + Carboplatin + Etoposide) and 1 patient received chemotherapy in the CDDP+CTX+VCR (Cyclophosphamide + Cisplatin + Vincristine) regimen. All patients had episodes of neutropenic fever when they received chemotherapy, requiring hospitalization and use of an antibiotic treatment. Among the 8 patients analyzed, all died. CONCLUSIONS: Despite progress in treatment, AT/RT of the CNS disease or primary kidney disease associated with a lack of standardization in a regimen contributes to the dismal prognosis. There is a high mortality in patients with AT/RT, similar to that found in the literature.
Peripheral lipidomics analyses with ensemble machine learning predict response to neoadjuvant therapy in breast cancer.
Authors: Jiani Wang, Fei Ma, Xiaoying Sun, Jinsong Wang, Fengzhu Guo, Binliang Liu, Wenna Wang, Qing Li, Binghe Xu
Journal: Journal of Clinical Oncology (2022)

582 Background: Neoadjuvant therapy (NAT) is critical in the therapeutic strategy for locally advanced breast cancer (BC) patients. Biomarkers to predict the pathologic complete response (pCR) and to screen beneficial responders need to be urgently explored. Lipidomics is a high-throughput analysis technique, which has potential applications for peripheral biomarkers’ detection to overcome the difficulty in serial pathological biopsies and tumor heterogeneity. Machine learning is a method for mining high-dimensional information with high group and low intermolecular correlation. Here we construct multidimensional models with machine learning approach combining clinical clinicopathological and lipidomics data to predict NAT response. Methods: Plasma samples were collected from 119 BC patients before after two cycles of NAT. Peripheral lipidomic profiles at multiple levels of lipid composition, concentration, chain length, and saturation were dynamically monitored by using absolute quantitative lipidomics. Responders (pCR) and non-responders (non-pCR) groups were randomly sampled in a 1:1.5 ratio for subsequent analysis. Screening of candidate lipidomic biomarkers were performed according to the criteria “VIP&gt;1, FC&gt;2 or FC&lt;0.5 and p&lt;0.05”. Above feature screening were validated by using ensemble machine learning algorithms (Logistic regression, Random forest and Support vector machine). Pearson correlation coefficients were calculated for the expressions of candidate biomarkers. Multidimensional prediction models with the logistic regression algorithm were constructed by correlating candidate lipidomics features with clinicopathologic phenotypes prospectively collected with baseline and dynamic changes. The performance of the models constructed above were assessed by ROC analysis. Results: A total of 8 major classes, 39 subclasses, and 2292 molecules of lipid metabolites were identified in the 235 plasma samples. Most of the candidate biomarkers had lower correlations, indicating lower overlapping and more optimal combination of panels. The prediction models constructed by baseline correlating candidate lipidomics features with ensemble machine learning achieved an Area under the Curve (AUC) of 0.84 for the training set and 0.72 for the validation set with the accuracy 0.84, the specificity 0.92, and the sensitivity 0.71 when the cutoff value is 0.57.The prediction models constructed with lipidomics dynamic changes also achieved good performance. Conclusions: The study suggested a possibility that peripheral lipidomics provided a potential tool to develop multidimensional models with ensemble machine learning for predicting response to NAT for BC patients with good discrimination power, which might guide individual optimal NAT strategies and avoid unnecessary treatment.
OTHR-06. Knowledge gap among health care providers in childhood central nervous system tumors: Result from an international multicenter survey
Authors: Revathi Rajagopal, Daniel C Moreira, Lane Faughnan, Huiqi Wang, Sameen Naqvi, Meenakshi Devidas, Ibrahim Qaddoumi
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Central nervous system (CNS) tumors in children are associated with a longer delay in diagnosis. One of the contributing factors is the lack of awareness regarding childhood CNS tumors presentation among health care providers. To evaluate the knowledge gap among health care providers, we conducted a cross-sectional survey that was distributed globally. METHODS: The survey was disseminated to health care practitioners via electronic mail in November 2018 and it was closed in March 2020. The participants were asked to complete a pre-test survey, requested to view a CNS tumor education seminar, and subsequently complete a post-test survey. The survey had nine questions focusing on CNS tumor symptoms, pre-diagnosis symptom interval (PSI), and imaging indication. The knowledge gap was evaluated with pre-test and post-test scores. RESULTS: 889 pre-test and 392 post-test responses were received. The majority of the respondents were from Asia, with a percentage of 73.1% and 87.5% in pre-test and post-test respectively. For the pre-test, the median score for accurate answers was 40.0% (range:13.1-92.9%). Interestingly, a high rate of correctness was achieved in the post-test with a median score of 77.1% (14.9-98.2%). In the pre-test, only 18.7% of the participants responded precisely that Cushing’s triad is a less common symptom and just 15.0% recognized that older children &amp;gt;10 years old are at risk for late diagnosis. Surprisingly, 21.9% falsely reported that patients with malignant tumors experience the longest PSI, and 54.5% of the respondents wrongly selected medulloblastoma as the commonest CNS tumor. Overall, the pre-test scores among pediatricians and professionals with &amp;gt;10 years of experience did not demonstrate improved knowledge when compared to other specialties. CONCLUSIONS: The survey analysis showed a significant knowledge gap regarding childhood CNS tumors among health care providers. Therefore, raising professional awareness is very important and can be achieved through targeted educational strategies.
Clinical efficacy and safety of individualized pembrolizumab administration based on pharmacokinetic in advanced non-small cell lung cancer: An open-label, single-arm, exploratory clinical trial.
Authors: Na Wang, Lie Zheng, Meichen Li, Xue Hou, Baishen Zhang, Jing Chen, Likun Chen
Journal: Journal of Clinical Oncology (2022)

e21161 Background: Pembrolizumab with or without chemotherapy has become the standard therapy in advanced non-small cell lung cancer (NSCLC), with a fixed dose of 200mg every 3 weeks. We performed this study to explore the clinical efficacy and safety of pharmacokinetic (PK)-guided pembrolizumab administration in advanced NSCLC. Methods: In this prospective, open-label, single-arm exploratory study, we enrolled advanced NSCLC patients without sensitizing EGFR or ALK mutation in Sun Yat-Sen University Cancer Center. Eligible patients received pembrolizumab 200mg every 3 weeks with or without chemotherapy for four cycles, then for patients without progressive disease, pembrolizumab was administrated in new dose-intervals (T) until disease progression. We set the effective concentration (C e ) at 15μg/ml and new dose-intervals (T) was calculated according to steady state plasma-concentration (C ss ) of pembrolizumab using following equation: C ss × 21D = C e (15μg/ml) ×T. Primary endpoint was the progression-free survival (PFS), secondary endpoints were objective response rate (ORR), and safety. Besides, advanced NSCLC patients who regularly received pembrolizumab 200mg 3-weekly until disease progression and more than four cycles in our center were respectively enrolled as the history-controlled cohort. Patients with C ss of pembrolizumab also underwent genetic polymorphism analysis of variable number of tandem repeats region (VNTR) in neonatal Fc receptor (FcRn). This study is registered at Clinicaltrials. gov, NCT05226728. Results: Between Nov 2019 and Dec 2020, total 58 patients were enrolled and received pembrolizumab 200mg every 3 weeks with or without chemotherapy, and 33 patients further received pembrolizumab in new adjusted dose-intervals according to C ss after four cycles. The C ss of pembrolizumab ranged from 11.01 to 61.21 μg/ml, 30 patients need prolonged intervals (22-80d) and 3 shortened intervals (15-20d). In PK-guided cohort, the median PFS was 15.1 months (95%CI 10.2-20.0 months) and ORR 57.6%, whereas the median PFS in history-controlled cohort was 7.7 months (95% CI 5.1-10.2 months) and ORR 48.2%. The immune-related adverse events occurred in 15.2% of patients in PK-guided cohort and 17.9% of patients in history-controlled cohort. The VNTR3/VNTR3 genotype of FcRn had significantly higher C ss of pembrolizumab than VNTR2/VNTR3 ( p= 0.005). Conclusions: PK-guided pembrolizumab administration showed promising clinical efficacy and manageable toxicity, which provided an alternative rational therapeutic strategy of pembrolizumab in advanced NSCLC. Clinical trial information: NCT05226728.
OTHR-16. Nutritional screening of U.S. pediatric central nervous system tumor survivors
Authors: Jacqueline Soja, Rebekah Wilson, Alexandra Yunker, Rahela Aziz-Bose, Erin Gordon, Christina Dieli-Conwright, Tabitha Cooney
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Adult survivors of pediatric central nervous system (CNS) tumors are at the highest risk for morbidity and late mortality among all childhood cancers – owed in part to chronic health condition burden, which intersects with environmental and lifestyle factors. Their weight epidemiology has not been previously characterized. METHODS: An institutional, cross-sectional study was carried out amongst young adults ages 18-39 years, previously treated for pediatric CNS tumors and seen in our specialty survivorship clinic from January 2016 to December 2021. Sociodemographic, clinical, and treatment information was extracted from medical records and summarized by descriptive statistics. Anthropometric information extracted from clinical visit records was used to calculate body mass index (BMI) and weight status category according to CDC guidelines. RESULTS: We identified 200 survivors, 47% male and 53% female. Median age was 26 years (range 18-39); patients were median 16.5 years (range 1.5-34.2) from initial diagnosis. Most common primary diagnoses were low grade-glioma (51.0%) and embryonal tumor (20.5%.) One hundred and five (52.5%) survivors had received prior cranial radiation; 81 (40.5%) had an endocrinologic disorder at time of visit. Amongst the entire cohort, 39% were healthy weight, 5% were underweight, 27% overweight, 21% obese, and 8% severely obese. CONCLUSION: The majority of young adult survivors seen in our clinic were not healthy weight by BMI definition. The distribution of BMI groups appears comparable to contemporary studies of the general young adult U.S. population. For those with decreased muscle mass, a previously recognized issue in pediatric CNS tumor survivors, BMI may underestimate body fat. By abstract presentation, univariable analyses will be performed using the Fisher’s exact test or Wilcoxon rank sum test to assess for undernutrition and overnutrition risk factors. Our refined understanding of the nutritional epidemiology in this population will allow for more strategic diet and exercise interventions.
MEDB-67. Subgroup specific analysis of cellular metabolism in medulloblastoma
Authors: Viktoria Funke, Carolin Walter, Viktoria Melcher, Lanying Wei, Sarah Sandmann, Julian Varghese, Natalie Jäger, Thomas K Albert, Ulrich Schüller, Kornelius Kerl
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Molecular subgrouping of Medulloblastoma (MB) has expanded our understanding of its biology and the impact on clinical parameters. However, detailed analysis of inter- and intratumoral heterogeneity on a metabolic level is currently lacking. Within this study, we aimed at improving our understanding of metabolic heterogeneity between the MB subgroups, between samples within these subgroups and how these differences affect prognosis. METHODS: We analyzed metabolic characteristics of four MB cohorts covering 1,804 samples in total. In 911 samples (ICGC and MAGIC cohort), we explored metabolic programs on RNA level. In two cohorts (ICGC and G3/G4 samples from the HIT cohort; n=1,035) we examined genetic alterations on DNA level. Furthermore, single-cell RNA-sequencing data of six samples were used to explore intratumoral metabolic heterogeneity. Inter- and intratumoral heterogeneity were correlated to clinical data. RESULTS: Using publicly available gene signatures, we discovered significant differences in metabolic gene expression comparing established MB subgroups. Three metabolically distinct clusters of G3/G4 samples could be defined by unsupervised analyses in two independent cohorts. We were able to confirm our finding of intertumoral metabolic differences on single-cell RNA level. Additionally, our analysis revealed the possibility of sample-specific metabolic features. On DNA level, we identified regulatory genes with known role in MB development to be predominantly associated with lipid metabolic processes. After all, lipid metabolism and metabolism of nucleotides in MB have prognostic value and correlate with the outcome of patients. CONCLUSION: Our data highlight the importance of metabolic properties in MB. We show the distinct metabolic signatures are clinically relevant and, thus, might provide opportunities for novel target-directed therapeutic options in the future.
NFB-23. Extent of tumor but not location may be predictive of longitudinal disease severity in children with NF1-associated gliomas requiring treatment
Authors: Sneha Chaturvedi, Arohi Saxena, Ahmad Hassan, Nicole Brossier
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Children with Neurofibromatosis Type 1 (NF1) are at risk for developing gliomas in multiple locations, particularly the optic pathway and brainstem. The goal of this study is to determine if glioma location in NF1 impacts tumor progression and accumulation of neurological deficits over time. METHODS: Retrospective chart review of 98 pediatric patients with NF1-associated gliomas between 1999-2021 at St. Louis Children’s Hospital. Patients who had never received treatment were excluded from analysis. Each glioma was categorized into one of four locations: posterior fossa (PF, n=12, 21%), supratentorial midline (SM, n=33, 57%) supratentorial cortical (SC, n=4, 7%), brainstem (BS, n=9, 15%). Patients with gliomas in different locations had each tumor counted separately (58 total gliomas analyzed). RESULTS: No SC tumors progressed. Time to first progression was comparable across the other 3 locations, and there was no meaningful different in neurologic deficits over time by tumor location. The majority of patients who demonstrated three or more clinical or radiographic progressions had tumors in the SM region. Within the SM tumor group, each tumor was further characterized as a deep extensive glioma (DEG; 36%) or an optic pathway glioma without deep extension (nonDEG; 64%). DEG had a slightly higher number of neurological deficits at baseline (DEG 2.08, nonDEG 1.19), fewer patients with no neurologic deficits (8.3% DEG vs 28.6% nonDEG) and a higher proportion of patients with a first progression event (41% DEG vs 24% nonDEG). However, DEG and nonDEG had similar risk of subsequent progressions after the initial event. CONCLUSION: Among children with NF1 who required glioma treatment, location was not a significant predictor of multiple progression or neurologic morbidity over time. Within the SM location, DEGs represent a newly characterized group that exhibit potentially higher rates of progression and neurological deficits. Multi-institutional analysis is needed to confirm these findings.
Driver coexistence characteristics of ALK-fusion in Chinese patients with lung cancer.
Authors: Min Gao, Yu Fang, Xiaoyan Zhang, Bin Wang, Meng Wang, Li Hua, Tonghui Ma
Journal: Journal of Clinical Oncology (2022)

8530 Background: ALK fusions and other driver mutations are usually mutually exclusive. With the widespread application of genetic testing techniques, the coexistence of ALK fusions and other driver mutations could be detected, such as ALK fusion and EGFR driver mutations. However, there were no systematical studies about the coexistence of ALK fusions and other driver mutations. Here, we retrospectively investigated the coexistence of ALK fusions and other driver mutations. Methods: Samples with ALK fusions were extracted from a Chinese lung cancer cohort, which from OncoPanscan (Genetron Health) based sequencing of tissue. Driver mutations of EGFR, ROS1, RET, NTRK1/2/3, BRAF, MET, KRAS and ERBB2 could be detected. Results: In the cohort, 692 samples with ALK fusions contained the intact kinase domain. These samples could be classified into three forms: canonical fusions (only EML4 partner, n = 601), single non-canonical fusions (only non- EML4 partner, n = 51) and complex non-canonical fusions (two or more partners, n = 40). Among the 692 samples, only 20 samples (20/692, 2.89%) coexisted with other driver mutations, which indicated that the driver coexistence were rare. 70% (14/20) of driver coexistence were happened on canonical fusions ( EML4-ALK) samples. They were coexisting with EGFR L858R (3), EGFR L858R plus ROS1 fusion (1), EGFR L858R plus MET amplification (1), KRAS G12C/D/V (3), MET amplification (3), MET Exon14 skipping (1), ERBB2 amplification (1), and MET amplification plus ERBB2 amplification (1), respectively. 20% (4/20) of driver coexistence samples were single non-canonical ALK fusions coexisting with EGFR 19del (1) or 20ins (1) or L858R (1) or MET amplification (1). Another 10% (2/20) samples were complex non-canonical ALK fusions coexisting with EGFR G719S (1) or RET fusion (1). Most co-mutations have corresponding targeted inhibitors, maybe these patients can be treated by combined or sequential therapies. Among canonical fusions, single non-canonical fusions and complex non-canonical fusions of ALK, the frequency of the samples without coexistence of driver mutations was respectively 97.67% (587/601), 92.16% (47/51), 95.00% (38/40), without significant difference (P = 0.056). Maybe single/complex non-canonical fusions are also strong drivers as canonical fusions. Conclusions: In this cohort, very few of ALK fusion patients coexisted with other driver mutations. Among the co-existence samples, ALK fusion were mainly coexisting with the site mutations of EGFR and KRAS, amplifications of MET and ERBB2, fusions of ROS1 and RET. These samples maybe obtain more effective outcomes by combined or sequential therapies.
A novel analysis of data from the PALOMA-3 trial confirms the efficacy of palbociclib and provides an option for efficacy assessments that could accelerate drug approvals.
Authors: Celine Yeh, Mengxi Zhou, Neil Bapodra, Maria Rivero, Edward Jose Espinal Dominguez, Marina Moran, Dawn L. Hershman, Antonio Tito Fojo, Susan Elaine Bates
Journal: Journal of Clinical Oncology (2022)

1069 Background: Advances in breast cancer (BC) therapy the past few decades have led to higher survival rates. Beginning with palbociclib, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have emerged as a treatment option for BC. We analyzed data from PALOMA 3 that could release a biomarker of OS in patients that receive palbociclib. Methods: We estimated concurrent rates of growth ( g) and regression ( d) from the 393 women with advanced BC enrolled in PALOMA-3 who had radiographic tumor measurement data including 261 treated with fulvestrant + palbociclib, and 132 with fulvestrant + placebo. We analyzed data using a model defined as SLD (t) = exp (– d x t) + exp ( g x t) – 1, where SLD = sum of longest diameters and t = time. We examined the relationship between g and overall survival (OS) and compared the median growth rates ( g) of various cohorts. Results: g values associate highly with OS (p&lt;0.0001). Emulating results in the clinical trial, palbociclib slowed the median g values of the entire population and those with sensitivity to previous endocrine therapy but not those deemed resistant. Further cohort analyses found greater benefit with palbociclib in those with visceral metastases, and longer disease-free interval, and benefit independent of ECOG PS, menopausal status, prior lines of therapy, and age. With only the baseline and two additional scans obtained, the median g values of the palbociclib and placebo arms were statistically different: p=0.038 after 28 (19/9) patients and p=0.0043 after 40 (26/14) patients. Conclusions: Estimates of palbociclib’s impact on tumor growth rates ( g) confirm its efficacy in PALOMA 3. Our ability to discern differences in g, a value associated with OS, after only two follow up scans in as few as 28 patients merits considering g an early biomarker of OS benefit that could bring effective drugs to patients as rapidly as possible. [Table: see text]